GCP violation and tampering with evidence

Last week, biotech company BioXcel reported positive efficacy results of their investigational product Igalmi in the treatment of Alzheimer's Agitation, but the supposed good news was shadowed by data integrity issues. On the same day, the company revealed allegations that an investigator had failed to adhere to trial protocol and was alleged to have fabricated emails to cover their tracks.

See the article "Missed trial protocols, fabricated emails and failed endpoint mar BioXcel's Alzheimer's agitation readout".

The company filed Form 8-K and revealed the GCP violation issues. Here are the excerpts from the SEC filing: 

          Important Information Regarding TRANQUILITY II Phase 3 Clinical Trial 

In December 2022, the U.S. Food and Drug Administration (“FDA”) conducted an inspection of one of the clinical trial sites in the Phase 3 TRANQUILITY II clinical trial, where the principal investigator enrolled approximately 40% of the subjects participating in the trial. At the conclusion of this inspection, the FDA issued an FDA Form 483 identifying three inspectional observations. These observations related to the principal investigator’s failure to adhere to the informed consent form approved by the Institutional Review Board for a limited number of subjects whose records the FDA reviewed, maintain adequate case histories for certain patients whose records the FDA reviewed, and adhere to the investigational plan in certain instances. For example, the FDA cited the principal investigator’s delay in informing the sponsor’s medical monitor or pharmacovigilance safety vendor of a serious adverse event (“SAE”) for one of the subjects, which report was made to the Company’s vendor outside of the 24 hour time period prescribed by the clinical trial protocol. The principal investigator for this clinical site responded to the FDA observations within the time period requested. The FDA inspection remains open, however, as the FDA has not issued an Establishment Inspection Report. 

In May 2023, it came to the Company’s attention that this same principal investigator in the TRANQUILITY II clinical trial may have fabricated email correspondence purporting to demonstrate that the investigator timely submitted to the Company’s pharmacovigilance safety vendor a report of an SAE from a different subject than the one cited in the FDA Form 483, and purporting to show that the vendor had confirmed receipt. Upon receipt of this information, the Company promptly initiated an investigation and recently received confirmation that the principal investigator fabricated the email correspondence related to the timing of the reporting of this SAE to the Company’s pharmacovigilance vendor to make it appear as though this SAE had been timely reported to the pharmacovigilance vendor as required by the clinical trial protocol. The Company also confirmed that this SAE had been timely entered into the electronic data capture system, even though the SAE had not been separately reported to the Company’s pharmacovigilance safety vendor within the 24 hour timeframe required under the protocol. 

In connection with this ongoing investigation, the Company was made aware that the fabricated email correspondence was provided to the FDA by the principal investigator’s employer during the on-site inspection in December 2022. After unblinding of the data, the Company determined that the SAE that was the subject of this fabricated correspondence between the principal investigator and the Company’s pharmacovigilance vendor occurred in a subject in the placebo arm. This principal investigator has not participated in any other clinical trial sponsored or conducted by the Company. Moreover, the study was designed such that trained study staff other than principal investigators were to conduct assessments of the primary efficacy measure.

In this case, the fabrication of evidence to hide the late reporting of the SAE to the sponsor is far more serious than the late reporting of the SAE itself. The situation is similar to tampering with evidence and obstruction of justice in the criminal law. 

ICH E6 Good Clinical Practice requires the investigational site to report the serious adverse events (SAEs) to the sponsor in a timely manner usually within 24 hours when the site staff become aware of the occurrence of an SAE. Failure to do so will be recorded as a major protocol deviation. 

However, fabricating the evidence to conceal the protocol deviation (late reporting of the SAE) is no longer a GCP compliance issue, it is a scientific misconduct issue.